Advances in dyslipidemia management for prevention of atherosclerosis: PCSK9 monoclonal antibody therapy and beyond

Abstract

The most significant advance in clinical cardiology and lipidology this decade is the emergence, and availability, of proprotein convertase subtilisin kexin type 9 (PCSK9) monoclonal antibody (mAb) therapies. Not since statin therapies became available nearly three decades ago has there been as much excitement and hope for the efficacious management of dyslipidemia and reduction of atherosclerotic cardiovascular disease (ASCVD) mAbs (alirocumab and evolocumab) were marketed in the United States, Europe, and other countries. In a wide range of high risk patients, with and without ASCVD, these PCSK9 mAbs, as once or twice monthly subcutaneous injections, potently reduce LDL-C 50-65% beyond levels achieved by maximally tolerated statin therapy; approximately one-third of patients achieve LDL-C levels <25 mg/dL. In the US, PCSK9 mAb therapy has current limited indications for persons with ASCVD or familial hypercholesterolemia requiring additional LDL-C reduction beyond maximally tolerated statin therapy. The first of the ASCVD outcomes-driven trials, the FOURIER trial has very recently shown in over 27,000 subjects randomized to evolocumab or placebo on top of moderate or high intensity statin therapy, a 15% risk reduction in the primary and 20% reduction in the secondary outcome over 2.2 years of treatment. Also of interest in patients with coronary artery disease on statin therapies, once-monthly evolocumab treatment, for only 76 weeks, resulted in significant plaque atheroma volume regression, as assessed by serial intravascular ultrasonography imaging, in approximately two-thirds of treated patients. Finally, in development is a highly durable RNA interference therapeutic inhibitor of PCSK9 synthesis which from a single dosage has been shown to maintain, for 6 months, a 75% reduction in PCSK9 levels and 50% reductions in LDL-C levels.The potential role of this vaccination-like product, as well as currently available PCSK9 mAb therapies, represents significant therapeutic advances to address ASCVD residual risk.

Post-transcriptional Regulation of PCSK9 by miR-191, miR-222, and miR-224

“…Hence, PCSK9 has been considered as a new target for hypercholesterolemia treatment. Most current strategies are based on PCSK9 protein level reduction using monoclonal antibodies and gene silencing methods (Sinning and Landmesser, 2017 ; Wong et al, 2017 ).…”

Pragmatic Analysis of Dyslipidemia Involvement in Coronary Artery Disease: A Narrative Review

“…( 1 ) shows how PCSK9 can influence lipid metabolism regulation [ 32 - 39 ]. A gain-of-function mutation for PCSK9 was found in families with FH [ 40 ].…”

“…In addition, evolocumab associated with statin treatment reduced cardiovascular risk in primary prevention with 15% and in secondary prevention with 20% during a 2.2 year treatment period. Moreover, an important regression of atherosclerosis plaque volume was observed after 76 weeks of evolocumab treatment in about two-thirds of patients [ 40 ]. Patients with statin treatment, as previously lipid-lowering therapy, who failed to reach the therapeutic targets, were later given 75 mg of alirocumab every two weeks in association with a statin.…”

Treatment Strategy for Dyslipidemia in Cardiovascular Disease Prevention: Focus on Old and New Drugs

“…Evolocumab selectively binds PCSK9 and prevents its binding with the LDLR ( Figure 1 ). Evolocumab results in a reduction in circulating PCSK9, LDL-C, total cholesterol (TC), ApoB, and non-HDL cholesterol, and an increase in HDL-C and Apo11 in patients with primary hypercholesterolemia and mixed dyslipidemia [ 55 , 56 ].…”